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We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

The symptom overlap between posttraumatic stress disorder (PTSD) and other pharmacotherapy-responsive disorders suggests that pharmacotherapy might be effective. Nevertheless, of the eight published placebo-controlled trials investigating the pharmacotherapy of PTSD, only four found statistically significant efficacy for the treatment being studied. This literature possesses a number of methodologic limitations, including the fact that most studies have been conducted with war veterans, who may constitute a more treatment-refractory population. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in some or all core PTSD symptoms (reexperiencing, avoidance, numbing, and hyperarousal). The authors hypothesized that paroxetine might be effective in PTSD, based on findings of its particular efficacy for anxiety and agitation in studies of depressed patients. The study presented here summarizes a 12-week, open-label trial of paroxetine among patients with noncombat-related, chronic PTSD. Outcome was assessed by an independent evaluator, the treating physician, and the patient, with the use of established rating scales for depression, anxiety, general symptoms, and PTSD core symptoms. A repeated-measures analysis of variance revealed highly significant improvement in all three symptom clusters, as well as in associated anxiety, depressive, and dissociative symptoms, with 11 of 17 (65%) patients rated as much or very much improved. The mean reduction in PTSD symptom scores was 48%. Exploratory analyses revealed that cumulative childhood trauma was negatively correlated with pharmacotherapy response (r = -0.52, p = 0.03). There was also significant variation in the time course of response across symptom clusters, which is suggestive of multiple mechanisms of response. Because paroxetine seems a highly promising treatment for all three symptom clusters of PTSD, a placebo-controlled clinical trial is warranted.

Some forms of anxiety and affective disorder, such as panic disorder and major depression, appear distinct, while other forms, such as generalized anxiety disorder and chronic depression or dysthymia, may lie on a continuum and blend with each other. However, even panic disorder and major depression have many common features. Moreover, for reasons not yet clear, they occur together frequently, and their combined occurrence in the same patient has been associated with greater severity and chronicity, decreased treatment responsiveness, and, possibly, increased familial prevalence of anxiety and/or depression. Finally, studies of primary care patients suggest the frequent occurrence of a mixed anxiety-depressive disorder that may often be subsyndromal by DSM-III-R criteria but is nevertheless associated with prominent distress and/or impairment.

Twenty-five patients with a primary DSM-III-R diagnosis of panic disorder with or without agoraphobia were treated openly with the serotonin uptake inhibitor fluoxetine for up to 12 months. For most patients, treatment was initiated at 5 mg/day to minimize adverse effects previously reported with initiation at higher doses. Nineteen (76%) experienced moderate to marked improvement in panic attacks. Four (16%) were unable to tolerate fluoxetine due to adverse effects. Initiating treatment of panic disorder with low doses of fluoxetine may increase its acceptability and permit more patients to benefit from fluoxetine.

The DSM-III-R excludes persons with socially phobic symptoms secondary to axis III conditions from the diagnostic category of social phobia. This exclusion exists without empirical basis. A series of eight clinical cases is presented in which patients suffered from excessive levels of secondary social anxiety relative to their disfiguring or disabling physical conditions. All subjects had a good response to the monoamine oxidase inhibitor phenelzine, which enabled them to live in a less-inhibited and less-restrictive manner. Their medication response to monoamine oxidase inhibitors parallels the psychopharmacologic response patterns of generalized or DSM-III-R social phobics. This study suggests a novel application of the drug phenelzine for a patient group formerly overlooked with regard to treatment options. The similarity of this group's psychopharmacologic responsivity and clinical characteristics to those of DSM-III-R social phobics also lends support to the relaxation of the axis III exclusion in DSM-IV's definition of social phobia.

Hypochondriasis without concomitant depression is often considered to be unresponsive to pharmacotherapy. Given marked similarities between hypochondriasis and obsessive-compulsive disorder, we decided to conduct an open trial of high-dose fluoxetine for patients with DSM-III-R hypochondriasis who did not meet criteria for major depression. Ten of 16 patients were much improved at the end of 12 weeks. A comparison of baseline and week 12 scores by the use of a paired-samples t-test revealed a statistically significant reduction in hypochondriacal concerns, as measured by the Heightened Illness Concern Clinical Global Impression Severity scale, the Whiteley Index of Hypochondriasis, and the Heightened Illness Concern Questionnaire. These results suggest that fluoxetine may be a useful therapy for hypochondriacal patients without marked depressive features--a group previously considered to be treatment refractory.

The novel anxiolytic agent buspirone has been shown to be effective in generalized anxiety disorder, but its utility in phobic disorders is less clear. We examined its efficacy in social phobia in a 12-week open trial. Twenty-one patients who met DSM-III-R criteria for social phobia and who did not respond to 1 week of single-blind placebo were treated with buspirone, and 17 completed a minimum of 2 weeks of treatment. Twelve of these 17 patients met criteria for the generalized subtype of social phobia. At week 12, 8 (47%) of the 17 patients were rated much to very much improved in social phobia symptoms on the Clinical Global Impression Scale. Of the 12 patients who were able to tolerate a dose of 45 mg/day or more, 9 (67%) were at least much improved. Significant improvement was noted on measures of social anxiety and avoidance of social situations. Ratings of generalized anxiety and depression, which were low at baseline, did not change significantly during treatment. The results suggest that buspirone may have modest efficacy in the treatment of social phobia, but confirmation in a placebo-controlled trial is required.

Alpidem, an imidazopyridine that acts at the gamma-aminobutyric acid/benzodiazepine receptor complex, has been reported to be an effective anxiolytic with a more favorable side effect profile than benzodiazepines. The effect of alpidem was investigated in an 8-week, open, clinical trial in 13 patients with panic disorder, with or without agoraphobia. Three patients were responders (much improved or very much improved), five patients were nonresponders, and five patients dropped out after less than 6 weeks of treatment. Significant improvement was seen in the sample as a whole for spontaneous panic attacks, phobic avoidance, and anticipatory anxiety. Most improvement occurred during the first 4 weeks of treatment, and responders had milder panic disorder at baseline. Adverse effects were generally mild. After 8 weeks of treatment, taper of medication over 2 weeks occurred without significant worsening of panic disorder symptoms. The efficacy of alpidem in the treatment of panic disorder remains uncertain and requires assessment in a controlled trial.

We report six cases of rapid mood cycling induced by antidepressant treatment. The key to effective treatment involved the recognition of the pattern of apparent remission, relapse, antidepressant and/or stimulant adjustment, remission, relapse, etc. Hypomanic episodes were frequently mild and could be mistaken for remission. The destabilizing effects of antidepressant drugs were not corrected by the addition of mood stabilizers, necessitating the withdrawal of the antidepressant agent. All but one case responded to such withdrawal. Two cases required the addition of high-dose L-thyroxine for stabilization. Implications for an effective treatment protocol are discussed.

Eight patients with depersonalization disorder or with depersonalization symptoms in association with obsessive-compulsive and panic disorders were treated with serotonin reuptake blockers. There was clinical overlap of depersonalization disorder with obsessive-compulsive disorder, and the co-occurrence of obsessive-compulsive and panic features with depersonalization in these patients was associated with a favorable treatment outcome. The chronicity of illness and lack of prior response to a variety of treatments in these patients highlights the positive outcome with this treatment. In addition, issues are raised regarding the current hierarchical exclusion of depersonalization disorder in the presence of obsessive-compulsive and panic disorders.

Clinical lore suggests that monoamine oxidase inhibitors (MAOIs) are not effective in endogenous depression. A review of previous placebo-controlled trials of MAOI in patients with endogenous depression neither refutes nor confirms their utility in this patient group. We present patients in the depressive phase of bipolar illness refractory to treatment with tricyclics who have responded to MAOI. These open trials require confirmation in controlled studies. Bipolar illness may be a heterogeneous disorder. Presence or absence of X-linkage, low platelet MAO, or response to MAOI may indicate different forms of the disorder.

Social phobia is the least well studied phobic disorder of those included in DSM-III. Reports from the British literature indicate that the condition is a distinct one that usually begins in adolescence and affects males more often than females. Patients characteristically complain of somatic symptoms and a fear of humiliation when confronted with specific social stimuli. Ten social phobic patients were openly treated with the cardioselective, peripherally active beta-adrenergic blocking drug atenolol. Five patients had complete response and four had moderate response. Side effects were minimal. Atenolol appears to work in social phobic patients by reducing autonomic nervous system response to phobic stimuli.

Phenelzine was administered to 11 patients meeting DSM-III criteria for social phobia in open clinical trials. Seven of 11 showed marked improvement, while the remaining four experienced moderate benefit. These findings, which require replication in controlled trials, suggest that in addition to other actions, phenelzine has a direct effect in reducing interpersonal hypersensitivity.

Six patients developed symptoms of pyridoxine deficiency while taking phenelzine. All had low pyridoxine levels, five being abnormally low. In all patients, symptoms responded to the addition of pyridoxine while continuing the antidepressant.

An open clinical trial of alprazolam therapy of patients with panic disorder or agoraphobia with panic attacks was undertaken to clarify certain issues not resolved by previous studies. These included the proportion of patients who significantly improve with alprazolam; the relative time courses for improvement in panic attacks, anticipatory anxiety, and phobic avoidance; whether successful alprazolam treatment alters vulnerability to panic with sodium lactate infusion; and what factors predict response to alprazolam in panic patients. Thirty patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks completed a 12-week open clinical trial, and 22 were considered responders. In responders, panic attacks showed rapid improvement, whereas improvement of anticipatory anxiety and phobic avoidance was more variable. Successful alprazolam therapy appeared to block lactate vulnerability. High pretreatment Hamilton Anxiety Scale scores were associated with poor treatment response. The data suggest that alprazolam is an effective treatment for panic disorder and agoraphobia with panic attacks, and acts by directly blocking panic attacks.

Fluoxetine is a new antidepressant with pharmacologic effects apparently limited to blockade of neuronal serotonin reuptake. We entered 20 patients who met DSM-III criteria for either panic disorder or agoraphobia with panic attacks into an open, uncontrolled pilot study of fluoxetine. Four responded to placebo in the week before fluoxetine administration and were dropped from the study. Of the remaining 16 patients, nine were nonresponders and seven were responders, with complete cessation of their panic attacks. Eight of the nine nonresponders were unable to tolerate the side effects of fluoxetine. In contrast, all of the responders (and one nonresponder) experienced minimal side effects. Fluoxetine may be effective in the treatment of panic attacks, perhaps implicating the serotonergic system in the pathophysiology of panic disorder. Future studies should use very low doses of fluoxetine to initiate treatment.

Effects of adjunctive clonidine (0.15 to 0.7 mg/day) on symptoms experienced during and for 4 weeks after gradual alprazolam discontinuation were observed in panic disorder patients after 6 weeks of successful treatment. Twelve of 14 entered patients were considered to have had a sufficient period of discontinuation (2 weeks) and clonidine administration (1 week) for effects to be assessed adequately. Nine of these 12 patients reached zero dose of alprazolam in 3 to 4 weeks. However, 10 of 12 patients experienced new withdrawal symptoms and 11 of 12 experienced recurrent panic attacks during tapering. Although a greater proportion of patients were successfully discontinued in a shorter time than in a previous nonclonidine trial, clonidine did not appear to have a specific effect on relapse or withdrawal. A placebo-controlled trial is needed to discriminate between possible contributions of clonidine and other factors (e.g., physician attitude, placebo effect of pill taking) to this improved outcome.

The selective serotonin reuptake blocker fluoxetine was administered to 49 patients with obsessive-compulsive disorder in a 12-week open clinical trial. A minimum adequate trial of at least 8 weeks of treatment was completed by 39 patients. Response rates were 62% (24/39) of adequately treated patients and 49% (24/49) of the whole sample. These uncontrolled findings suggest that fluoxetine is of significant benefit for a substantial proportion of obsessive-compulsive disorder patients. However, controlled trials comparing fluoxetine with placebo and other active agents are needed to confirm this, as are studies aimed to delineate fluoxetine's full dose range, optimal length of treatment and relapse rate following discontinuation.